The citric acid cycle is the central metabolic hub of the cell. It is the final common pathway for the oxidation of fuel molecule such as amino acids, fatty acids, and carbohydrates.

1. Graduate school of natural
and applied science
Biochemical technology
By:
Dr. Canan Can
Omeed akbar ali

2. CITRIC ACID CYCLE
 Introduction
 Site
 Pathway
 Energetics
 Regulation
 Clinical importance

3. INTRODUCTION
The citric acid cycle is the central metabolic
hub of the cell.
 It is the final common pathway for the
oxidation of fuel molecule such as amino acids,
fatty acids, and carbohydrates.
In eukaryotes, the reactions of the citric
acid cycle take place inside mitochondria,
in contrast with those of glycolysis, which
take place in the cytosol.

4. Definition :
 The citric acid cycle is a series of reactions that brings about
catabolism of acetyl-coA liberating reducing equivalents which
upon oxidation through respiratory chain of mitochondria, generate
ATP.
 It plays a central role in the breakdown or catabolism of organic fuel
molecules—i.e glucose and some other sugars, fatty acids, and some
amino acids. Before these rather large molecules can enter the TCA cycle
they must be degraded into a two-carbon compound called acetyl
coenzyme A (acetyl CoA). Once fed into the TCA cycle, acetyl CoA is
converted into carbon dioxide and energy.

5.  Takes place in the matrix of
the mitochondria.
 It happens once for every
pyruvate molecule in
glycolysis….
 Purpose
• Conversion of Acetyl-CoA to
CO2
• Generates reducing
equivalents (NADH + H+,
FADH2) & GTP to be oxidized
in the respiratory chain to
generate ATP

6. OVERVIEW
 Acetyl coA, the
precursor for fatty acid
synthesis is produced
from pyruvate, ketogenic
amino acids, fatty acid
oxidation and by alcohol
metabolism.
 It is a substrate for TCA
cycle and a precursor for
faty acids ketone bodies
and sterols.

7. STEPS INVOLVED IN TCA CYCLE

10.  TCA cycle is an open cycle
 Operates only under aerobic conditions
 This is the Final common pathway of oxidative
metabolism
 Two carbon dioxide molecules are released as a
waste product of respiration
GTP
+ H+

11. Energetics : 2 Acetyl CoA from 2 Pyruvate
 1NADH+H+ = 3/2.5 ATP
 1FADH2 = 2/1.5 ATP
 1GTP = 1 ATP
Acetyl-CoA + 3 NAD+ + [FAD] + GDP + Pi + 2 H2O CoASH +
3 NADH+3 H + +[FADH2] + GTP + 2 CO2
×2=24

13. ATP generation during oxidation of Glucose
Net ATP production depends on shuttle used for the transfer
of reducing equivalents from cytosol to mitochondria.
8 / 7
6 / 5
24 / 20
38 / 32

14. SIGNIFICANCE OF TCA CYCLE:
1. Complete oxidation of Acetyl CoA
2. As provider of energy
3. Final common oxidative pathway
4. Integration of major metabolic pathways
5. Fat is burned on the wick of carbohydrates
6. Excess carbohydrates are converted to Neutral fat
7. No net synthesis of carbohydrates from fat
8. Amino acids enters TCA cycle
9. Amphibolic pathway
10. Anaplerotic role

15. Bio medical importance
• Bioenergetics is the study of the energy
changes accompanying biochemical
reactions. Biologic systems are essentially
isothermic and use chemical energy to power
living processes.
• Animal obtains suitable fuel from its food to
provide the energy for metabolism.
• Death starvation

16. • Thyroid hormones control the rate of energy
release and disease results when they malfunction.
• Excess storage of surplus energy causes obesity.
• This cycle is a series of chemical intermediates.
• Each step is catalyzed by a specific enzyme.
Bio medical importance

17. Indicator molecules of
higher energy state i.e.
ATP, NADH, citrate, Acetyl
CoA – inhibit TCA cycle
Indicator molecules of
low energy state i.e. ADP,
AMP, NAD+ – stimulate
TCA cycle
*
*
*
*

18. a) Citrate synthase- There is allosteric inhibition of
citrate synthase by ATP and long-chain fatty acyl-CoA.
b) Isocitrate dehydrogenase- is allosterically stimulated
by ADP, which enhances the enzyme's affinity for
substrates. In contrast, NADH inhibits iso-citrate
dehydrogenase by directly displacing NAD+. ATP, too, is
inhibitory.

19. c) α-ketoglutarate dehydrogenase -α- Ketoglutarate
dehydrogenase is inhibited by succinyl CoA and
NADH. In addition, α-ketoglutarate dehydrogenase
is inhibited by a high energy charge. Thus, the
rate of the cycle is reduced when the cell has a
high level of ATP.
d) Succinate dehydrogenase is inhibited by
oxaloacetate, and the availability of oxaloacetate,
as controlled by malate dehydrogenase, depends
on the [NADH]/[NAD+] ratio.

20. INHIBITORS OF TCA CYCLE
1. Fluoroacetate
 Condensation FluoroacetylCoA with Oxaloacetate
Fluorocitrate inhibit Aconitase enzyme accumulation
of citrate
 Fluoroacetate pesticide
2. Malonate Succinate dehydrogenase enzyme
3. Arsenite α-ketoglutarate dehydrogenase enzyme

21. METABOLIC DEFECTS
• Extremely rare
1. Defect in PDH
- Lactic acidosis
- Neurologycal dosorders
2. Defect In Pyruvate carboxylase
- Oxaloacetate
- Hyperammonemia
- Lactic acidosis
- Hyperalaninemia.

22. WHY TCA IS CALLED AMPHIBOLIC?
It plays both catabolic and anabolic role.
*Catabolic role:
Acetyl CoA is oxidized to C02, H2O giving out energy.
*Anabolic role:
Intermediates of TCA cycle plays a role in synthesis like
heme formation, FA synthesis, Cholesterol, Steroid synthesis.

23. SUMMARY
• Pyruvate is converted to acetyl-CoA by the action
of p yruvate dehydrogenase complex, a huge
enzyme complex.
• Acetyl-CoA is converted to 2 CO2 via the eight-
step citric acid cycle, generating three NADH, one
FADH2, and one ATP (by substrate-level
phophorylation).

24. • Intermediates of citric acid cycle are also used as
biosynthetic precursors for many other
biomolecules, including fatty acids, steroids, amino
acids, heme, pyrimidines, and glucose.
• Oxaloacetate can get replenished from pyruvate, via
a carboxylation reaction catalyzed by the biotin-
containing pyruvate carboxylase.

25. THANK YOU